Review

Stress and anxiety across the lifespan: structural

plasticity and epigenetic regulation

The brain is the central organ of the bodys response to and perception of stress. Both the juvenile and
the adult brain show a significant capacity for lasting physiological, structural and behavioral plasticity as
a consequence of stress exposure. The hypothesis that epigenetic mechanisms might lie behind the lasting
effects of stress upon the brain has proven a fruitful one. In this review, we examine the growing literature
showing that stress has a direct impact on epigenetic marks at all life history stages thus far examined
and how, in turn, epigenetic mechanisms play a role in altering stress responsiveness, anxiety and brain

of
plasticity across the lifespan and beyond to succeeding generations. In addition, we will examine our own
recent findings that stress interacts with the epigenome to regulate the expression of transposable
elements in a regionally specific fashion, a finding with significant implications for a portion of the genome
which is tenfold larger than that occupied by the genes themselves.

ro
Keywords: adolescence n adulthood n aging n DNA methylation n early life n histone Richard G Hunter*1,2 &
modification n ncRNA Bruce S McEwen1
1
Harold & Margaret Milliken Hatch
Stressful experiences occur across the lifespan stimulation [7] , intense learning [8] , learning Laboratory of Neuroendocrinology,
rP
The Rockefeller University,
and have lasting effects on the brain, body and and practicing of motor skills [9] , and acute and 1230 York Ave., New York, NY 10065,
behavior [1] . Stress is a contributor to a variety chronic stressors [4] . Circulating hormones play USA
2
Department of Psychology, University
of disorders, including anxiety and mood dis- a role along with endogenous neurotransmitters of Massachusetts, Boston,
orders, but also diseases like heart disease and and trophic factors [4] . 100Morrissey Blvd, Boston, MA 02125,
USA
metabolic syndrome [2] . Stress also has the capac- In the hippocampus and medial prefrontal *Author for correspondence:
ho

ity to induce brain plasticity in a variety of ways,
including neurogenesis, and the structure of
neurons in stress-sensitive brain regions like the
hippocampus, amygdala and prefrontal cortex
[3] . Given the potential of stress to alter physiol-
ut
cortex, chronic stress causes dendrites of neu- richard.hunter@umb.edu
rons to shrink and become shorter and less
branched, with an accompanying reduction in
synaptic input [10,11] . This reduces capabilities for
nuanced cognitive function, memory and self-

ogy and behavior in a lasting way, particularly in
a terminally differentiated tissue like the brain,
many researchers made the logical conclusion
that the mechanisms behind the persistence of
A
regulation. Glucocorticoids of the adrenal cortex
and excitatory amino acid transmitters in those
brain regions participate in the depolymerization
of the cytoskeleton and shrinkage of dendrites,

such stress-induced alterations might be epigen-
etic in nature. This review will describe the work
that has begun to support this hypothesis, and
examine how stress and epigenetics interact in
the brain across the lifespan and across genera-
tions (see Table1 and Figure 1 for a schema of the
interactions of brain and behavioral plasticity
with epigenetic actors and stress).
Stress & brain plasticity
The brain possesses a life-long capacity for
reversible, structural plasticity, which includes
turnover of synaptic connections, expansion
and contraction of dendritic trees and a lim-
ited amount of neurogenesis, particularly in
the dentate gyrus of the hippocampus [4] . This
plasticity can be seen as a result of an enriched
environment [5] , regular exercise [6] , sensory
by a process that is largely reversible at the end
of stress, at least in the young adult brain [4,10] .
With aging, there is some loss of resilience that
is shrinkage of dendrites occurs, but recovery is
impaired [12] . In contrast to hippocampus and
the medial prefrontal cortex, the basolateral
amygdala and orbitofrontal cortex respond to
the same chronic stress by expanding dendrites
and increasing synaptic input, which leads to
increased anxiety, vigilance and aggressiveness
[13,14] . Early-life events also affect how these
brain regions develop, as will be discussed below.
Stress-induced changes in brain regions in
the animal models discussed above are mir-
rored by findings for the human brain that
include shrinkage of the hippocampus in pro-
longed major depression and Cushings disease,
as well as in post-traumatic stress disorder part of

10.2217/EPI.13.8 2013 Future Medicine Ltd Epigenomics (2013) 5(2), 1xxx ISSN 1750-1911 1
Review Hunter & McEwen

Table 1. Neuroepigenetic changes induced by stress across the lifespan.

DNA methylation Histone modifications ncRNA
Prenatal stress
GR 17, CRH [66] Altered miRNA to b-glycan [67]
11b-HSD [69]
Reelin, GAD67 [71]
DNMT1, 3A gene expression
Postnatal stress
GR 17 [82] H3K9ac [82]
AVP [101]
BDNF [105]
Adolescent stress

of
? ? ?
Adult acute stress & fear learning
Reelin, PP1 [122] H3Ac [121] , H3S10p-K14Ac [131] Retrotransposon RNA [155]

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BDNF [123]
DNMT 3a,b gene expression H3K9me3 miR-18, 24a effect GR [158,159]
[122] H3K27me3 [152]
DNMT inhibition impairs learning H3K4me, H3K27me [153] mir34c [161]
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HDAC inhibition improves
learning
Adult chronic stress
DNMT3a gene expression [149] Altered H3K9/K27 methylation miR-186, 709 region-specific
[149] changes [163]
ho

CRH [148] H3K27me3 (social defeat) [143] miR-29bc, 212, 410, 708
chronic sleep deprivation [164]
miR-22, 99a, 137, 2172, let7e
[164]

Aging stress
ut

? ? ?
DNA methylation changes refer to gene promoters or enhancers showing changes in methylcytosine levels, or in
expression of DNA methyltransferases (DNMT). Histone modifications refer to global changes in a particular histone mark
in a part of the brain. The column for ncRNA refers to changes observed in the levels of various ncRNAs such as miRNAs
(e.g.,miR, let) or transcripts from transposable elements.
A

(PTSD) and Type2 diabetes [15] . In PTSD, a
smaller hippocampus, possibly a reflection of
low self-esteem [16] , is recognized as both a risk
factor for PTSD, as well as a target of chronic
stress associated with PTSD [17] . There is also a
smaller hippocampus reported in chronic jet lag
[18] , as well as after a 20-year history of chronic
perceived stress, and also with increased levels
of systemic inflammation, as well as a lack of
exercise. The amygdala is more active in anxiety
disorders and depression, while the prefrontal
cortex becomes less efficient with lack of exer-
cise and also with higher levels of perceived
stress. Regular moderate exercise has been
shown to improve prefrontal cortical blood
flow and function in decision making and also
enlarge the hippocampus within a time frame
of 612 months [6,15] .
The human brain appears not only receptive
to favorable physical stimuli, but also to support-
ive relations and meaningful work throughout
life. Structural brain changes have been asso-
ciated with successful cognitivebehavioral
therapy [19,20] , and it has been suggested that
psychotherapy can be considered an epigenetic
intervention, alongside drug therapy [21] .
The health of a persons brain is not only
important for effective processing of inputs
from the external environment, it also controls
adjustments of the body engendered by behav-
ioral states like waking, sleeping, lying, standing
and exercising, and does so via the bidirectional

2 Epigenomics (2013) 5(2) future science group

 Stress & anxiety across the lifespan: structural plasticity & epigenetic regulation Review

Development

Stress
St

Histone
modification
DNA
methylation
Control
ncRNA

of
Translation,
mRNA stability Subordinate

Brain Epigenome Brain plasticity Behavior

ro
Figure 1. The brain is the principal perceiver of stress, and it in turn encodes stressful
experience epigenetically. Epigenetic changes alter brain function and brain plasticity, these in
turn alter behavior and cognition. The developmental period affects the brainenvironment
interaction at all levels.
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Adapted from [202] .

communication between the neuroendocrine,
autonomic, immune and metabolic systems and
the brain [10,22] . These adjustments in the body
promote adaptive activities, such as locomotion,
ho
stress of the mother can impair features of nor-
mal brain development [26] , and that prolonged
separation of infant from mother also impairs
other aspects of brain development and function

and promote coping with aversive situations and
discrete stimuli, such as noise, crowding, hunger,
excessive heat or cold, and other threats to the
persons integrity and safety. Therefore, changes
in the neural architecture of key brain regions
ut
[2729] . On the positive side, good maternal care
and consistency of that care is a powerful deter-
minant of life-long patterns of reduced anxiety
and efficient stress reactivity, as well as social
and cognitive development [3032] . Moreover, in

will affect how the person handles daily experi-
ences, so as to either increase or moderate how a
variety of experiences affect the rest of the body
and ultimately, the fate of the individual. The
A
rodents, there are transgenerational effects that
appear to be behaviorally transmitted by the
mother to the female offspring [33] , and involve
epigenetic modifications of glucocorticoid recep-

foundations of these interactions are established
early in life.
While the focus of this review is upon the
interaction of developmental history with stress,
brain plasticity and epigenetics, it is important to
note that biological sex has a significant influence
on all of these phenomena. Epigenetic factors,
in turn, play a role in the development of sex-
specific brain structural and functional dimor-
phism [2325] . This is of particular importance
to our translational understanding of these sub-
jects, given the substantial sex bias observed in a
number of brain disorders from autism to anxiety
disorders.
Early-life experiences become
biologically embedded
Animal models have taught us that prenatal
tors, among other genes [34] . In contrast, incon-
sistent maternal care and maternal anxiety, for
example, from food insecurity, produce anxiety
in offspring and appear to contribute to metabolic
syndrome and predisposition to diabetes, which
itself has adverse effects on the brain [35,36] . Thus,
the behavioral and physiological consequences
of early-life abuse and neglect are profound, and
the epigenetic concept of behavioral transmission
of abuse and its effects on human brain func-
tion are being explored at the level of epigenetic
regulation of gene expression[37] .
During recent decades, a number of studies
have documented that early-life adversity also
becomes bodily embedded in human fetuses
and children, with major implications for health
throughout the lifespan (for example, see refer-
ences[38,39]). Chronic dysregulation of adaptive

future science group www.futuremedicine.com 3

Review Hunter & McEwen
systems (allostatic overload), involving epigen-
etic mechanisms, shapes the developing brain
and bodys biological vulnerability to disease, as
well as its responsiveness to potential interven-
tions [22,40] . Of particular relevance for children
are experiences of abuse and neglect [41] . On the
physiological level, adverse childhood experi-
ences are associated with dysregulated cardiovas-
cular, metabolic and immunological function,
which in turn feed into numerous systemic and
behavioral disease conditions [41] . Chaos in the
home and inconsistent parenting impairs brain
development, and this can lead to disturbed cog-
nitive function, instable mood, low self-esteem
and numerous unhealthy activities, including
overeating, substance abuse, sexual acting-out
and other forms of legal or illegal risk-taking [42] .
For example, a 10-year history of a child grow-
ing up in a home where the mother has chronic
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depression is associated with the child having
a larger amygdala [43] . Furthermore, low self-
esteem and locus of control is associated with
a smaller hippocampus and a lesser ability to
turn off the cortisol stress response [16] . Children
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growing up without adequate verbal stimulation
and in chaotic, unstable home environments
are vulnerable to impaired cognitive function,
increased systemic inflammation, cardiovascular
disease, substance abuse, antisocial behavior and
ho
depression [4447] .
Neuroepigenetic effects of stress in
early life
It is well-established that exposure to environ-
ut
mental stressors in early life has lasting effects on
stress reactivity and hippocampal plasticity that
persist into adulthood. In humans, separation
from both parents during early life can have a
A
decades-long influence on hypothalamicpitui-
taryadrenal (HPA) axis reactivity and liability
to depression. Infants whose mothers suffered
from starvation during the Dutch famine dur-
ing World WarII had higher levels of depression
and schizophrenia, higher HPA axis reactivity
and twice the rate of cardiovascular disease
than the children of properly nourished moth-
ers [48] . These children also had reduced DNA
methylation of the IGF2 gene 60years later [49] .
More compelling, from the epigenetic perspec-
tive, are the findings that vulnerability to PTSD
and altered HPA axis reactivity can be passed
maternally to the children of Holocaust survi-
vors [50,51] . As these results suggest, severe stress-
ors in early life can have pronounced epigenetic
effects on the stress axis; however, different stress
modalities can have opposing effects on both
4 Epigenomics (2013) 5(2)
the stress axis and brain plasticity. For example,
more intense interventions, such as maternal
separation (MS) have a sensitizing impact on
the stress axis, while less severe interventions,
like neonatal handling or maternal exercise, can
promote increased resilience to stress in later life
[52,53] .
Prenatal stress
Stress and corticosteroid exposure during pre-
natal life also have the capacity to alter stress
responses, behavior and brain function in later
life [1,54,55] . Prenatal stress or glucocorticoid
treatment produce lasting behavioral changes
across the lifespan, including learning deficits
of
and increased depressive and anxious behavior
[56,57] . These effects are mediated in part by
their effects on stress-responsive brain regions
like the hippocampus, amygdala and prefron-
tal cortex, and include reduced dendritic spine
density and lower levels of hippocampal neu-
rogenesis [5861] . As with stressors at other life
stages, stress intensity influences the outcome
for the animal in later life. More severe stress-
ors produce exaggerated stress-evoked release of
corticosterone and impairments in hippocampal
function [6163] , while milder exposures produce
improved resilience [64,65] .
A number of recent studies have shown that
prenatal stress results in lasting effects on the
epigenome in a number of stress-sensitive brain
regions. It has been recently demonstrated that
prenatal stress causes hypermethylation of the
GR 17 promoter in the hippocampus and
hypomethylation of the CRH promoter in the
hypothalamus and central amygdala of adult
male mice, but not females. These differential
responses correlate with the expression of a
number of genes in the placenta, including the
DNA methyltransferases DNMT1 [66] ; although
these findings remain descriptive, they outline
an interesting area for continued research. Some
of the effects observed in this model were passed
onto the F2generation and were found to result
from altered expression of miRNAs targeting
the b-glycan gene [67] . The effects observed by
the Bale laboratory [66,67] resemble the effects
of maternal depression on GR methylation in
human infants [68] . Prenatal stress also has the
capacity to change the expression and DNA
methylation status of the corticosteroid meta-
bolic enzyme 11b-HSD2, and cause increased
DNMT3a expression in placenta and increased
DNMT1 expression in the fetal cortex [69] . In
humans, increased 11b-HSD2 methylation is
associated with slower newborn growth and
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 Stress & anxiety across the lifespan: structural plasticity & epigenetic regulation
aberrant behavior [70] . In mice whose dams
were subjected to restraint stress during gesta-
tion, increased expression of DNMT1 and 3a
and decreased RELN and GAD67 in prefrontal
and hippocampal GABAergic interneurons was
seen. The promoters of the reelin and GAD67
genes also showed increased DNA methylation
and hydroxymethylation. These mice also dis-
played increased locomotor activity, decreased
social interaction, impaired prepulse inhibi-
tion and poorer fear conditioning, which were
reversed by treatment with valproic acid (a his-
tone deacetylase [HDAC] inhibitor) or clozap-
ine (which has DNA demethylase activity) [71] .
Both the behavioral and transcriptional changes
observed in this model are consistent with those
observed in humans suffering from schizophre-
niaa disorder in which maternal stress and
gestational insults have a strong influence [72,73] .
Neonatal handling can also reduce the long-term
physiological and behavioral consequences of
prenatal stress [74] . These results suggest that
either pharmacological or structured behavioral
interventions in early life (e.g.,[75]) could have
substantial translational utility in ameliorating
the effects of prenatal stressors.
Postnatal stress
The best-established model for the epigenetic
ho
impact of early-life adversity is that based on
natural variations in maternal care in rodent
mothers. Michael Meaney and collaborators
have established that rodent mothers, which
exhibit high or low levels of arched back nurs-
ut
ing (ABN) and maternal licking and grooming
of pups (LG), produce offspring with differing
stress-related behavior and HPA reactivity in
adulthood, mediated in part by higher levels of
A
hippocampal GR and lower hypothalamic CRH
in the offspring of high LG-ABN mothers [7678] .
At the level of synaptic plasticity and learning,
low LG-ABN rearing produces shorter dendritic
arbors and lower spine density in the hippo
campus, but actually produces improved learn-
ing under stressful conditions [79,80] , a finding
consistent with the adaptive calibration model
of stress responsivity [81] . Most remarkably, these
effects were epigenetic in the strict sense in that
both the variations in stress reactivity and mater-
nal behavior were transmitted across multiple
generations.
The mechanism by which these transgenera-
tional effects occurred was outlined in detail in
a later paper produced by the Meaney group in
collaboration with the Szyf laboratory [82] . They
showed that the adult offspring of low LG-ABN
future science group
Review
mothers had higher layers of DNA methylation
at the 17 promoter of the GR in their hip-
pocampus than high LG-ABN offspring, and
that this change correlated with the behavioral
changes observed in the model. When pups
from low LG-ABN mothers were cross-fostered
to high LG-ABN dams, the methylation of the
17 promoter was reduced to levels equivalent
to those found in the natural offspring of those
dams. This demonstrated that the change was
dependent on maternal care rather than genetic
or inutero influences. The maternal behavior-
dependent methylation in the 17 promoter
was most clearly associated with that portion
of the promoter bound by NGFI-A (or egr1).
of
Chromatin immunoprecipitation of NGFI-A in
the hippocampus of 6-day-old pups showed that
binding to the 17 promoter was lower in low
LG-ABN pups than in high LG-ABN, although
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total NGFI-A protein levels remained the same
across groups. Low LG-ABN pups also showed
lower levels of histone acetylation at the 17 pro-
moter than high LG-ABN. HDAC inhibitors are
capable of both increasing histone acetylation
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levels and reducing levels of DNA methylation
[83] , so Weaver used hippocampal infusions of
the HDAC inhibitor trichostatin A in adult rats
to successfully reverse both the reduction in hip-
pocampal GR and the increased stress reactivity
found in low LG-ABN offspring [82,84] . This was
the first demonstration that a transgenerational
epigenetic change was reversible with a phar-
macological intervention, a finding with obvi-
ous implications for human mental disorders
associated with childhood abuse or neglect.
The human equivalent of the rodent 17 pro-
moter is the 1-F promoter [85] , and it too has been
shown to be hypermethylated in suicides with a
history of childhood abuse [86] ; a more recent
study demonstrated that these effects extended
to the expression and methylation of the 1-B,
1-C and 1-H promoters as well [87] . It should be
added that these findings are complex (1-H is
hypermethylated but the transcript is increased),
and that there are now a small body of stud-
ies (e.g.,[88]) that suggest simple connections
between GR methylation status and mental
disorders that may prove elusive. Childhood
adversity has also been shown to produce hyper-
methylation of the GR promoter in leukocytes
from normal adults, and this result was found
to correlate with a reduced cortisol response to
a dexamethasone CRH challenge [89] . Another
recent study using a genome-wide approach
found that a history of early-life adversity cor-
related with differential DNA methylation at
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Review Hunter & McEwen
362 separate promoters, and that this group was
enriched for genes involved in neuronal plasticity
[90] , further establishing that early-life adversity
in rodents and man has lasting epigenetic effects
on physiology and behavior.
While the LG-ABN is the best-known model
in which transgenerational epigenetic effects on
the stress axis are observed, such effects have
also been described in other model systems. For
instance, prenatal treatment with the synthetic
glucocorticoid, betamethasone, produces sub-
stantial alterations in the global DNA methyla-
tion status of both fetal organs and the placenta.
Betamethasone also changed the expression
levels of a number of epigenetically significant
genes, notably DNMT3b and Crebbp [91] . Inter-
estingly, some cases of transgenerational epigen-
etic effects in animal models appear to be trans-
mitted paternally rather than maternally. The
ro
Crews and Skinner laboratories have shown that
the antiandrogenic fungicide vinclozolin has
transgenerational effects on anxiety and stress-
evoked behavior [92,93] . These alterations seem
to be transmitted via the paternal germline by
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altered DNA methylation of the sperm genome
[94] . Another potential case of paternal epigenetic
inheritance has been described by Dietz etal.
[95] , who found that the offspring of socially
defeated fathers were more susceptible to sub-
ho
maximal defeat in adult life than the offspring
of control fathers. However, invitro fertilization
did not transmit the increased susceptibility to
defeat. One could conjecture that the effect
may relate to differential maternal investment
ut
based on perceived mate quality, but this has
yet to be established. A neonatal manipulation,
which shows both maternal and paternal trans-
mission, is lipopolysaccharide treatment, which
A
alters anxiety behavior and stress-evoked corti-
costerone to at least the F2generation. Maternal
transmission was blocked by cross-fostering, and
seems to occur via maternal behavior. However,
the mechanism of paternal transmission in this
model is, as yet, unclear [96] .
MS is another model of early-life stress and
adversity. MS paradigms typically involve sepa-
rating the pups from their dam for several hours
a day during the first 2weeks of post-natal life.
Like the LG-ABN model, MS can have trans-
generational effects on stress reactivity, although
it too appears to act via paternal transmission
[97] and have a differential effect on males and
females. Much like low LG-ABN rearing, MS
results in increased HPA reactivity and clear
effects on hippocampal synaptic plasticity and
learning in adulthood [29,98,99] . This is, in part,
6 Epigenomics (2013) 5(2)
due to increased adrenocorticotrophin release in
response to stress [100] , which is in turn under the
control of CRH and AVP secreted from the para-
ventricular nucleus of the hypothalamus. Mur-
gatroyd etal. examined paraventricular nucleus
expression of these two genes in MS animals and
found that MS increased AVP, but not CRH
expression. The change in AVP expression was
associated with DNA hypomethylation in an
enhancer region of the AVP gene bound by the
methyl CpG-binding domain protein MeCP2
[101] . MeCP2 is involved in the pathology of
Rett syndrome [102] , and has been shown to be
involved in the regulation of stress and plasticity
genes such as BDNF [103,104] . A similar model,
of
using stressed and abusive dams, caused a reduc-
tion in the expression of BDNF in the prefron-
tal cortex of the pups and this reduction was
correlated with hypermethylation of the exon
IV promoter of the BDNF gene. This change
was found to be reversible when the pups were
treated with the DNA methylation inhibitor
zebularine [105] . Although not linked to stress
perse, differences in anxiety in the high and low
response to novelty rat lines has been linked to
developmental differences in DNMT1 expres-
sion in the hippocampus and amygdala [106] ; as
these differences are found largely in the first
week of life, they are further evidence of the
epigenetic sensitivity of this life stage. The find-
ings reviewed here have firmly established the
power of postnatal environment to impact the
epigenome, the stress axis, behavior and synaptic
plasticity.
Adolescent stress
The adolescent life stage marks the transition
from the rapid growth that characterizes infancy
and childhood, towards the utilization of the
organisms energetic resources for reproductive
purposes. As such, it marks the point at which
most mammals turn outward from parental
attachments towards a wider social milieu. The
demands of that milieu are likely more severe in
animals with complex societies, such as human
beings. Adolescence is marked by a number
of changes in behavior, brain structure and
function [107] . It is also the time of life where
humans are most likely to develop a variety of
psychiatric disorders including substance abuse,
schizophrenia and depression [108] . Why this
is the case, when many of these disorders are
associated with stress exposure in earlier life, is
unclear. However, one could hypothesize that
the increased demand for social cognitive capac-
ity at this age could reveal pre-existing deficits
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 Stress & anxiety across the lifespan: structural plasticity & epigenetic regulation
in stress-sensitive regions, such as the amygdala,
which play a role in social learning [109] .
It is clear that adolescence is also a transition
in the development of the stress axis and upon
hippocampal plasticity [1,54,55] . Human adoles-
cents have increased basal and stress-evoked
HPA activity [110] , and peripubertal rats also
show a potentiation of adrenocorticotrophin
and corticosterone in response to stress [111,112] .
Most significantly from the perspective of
stress-induced plasticity, peripubertal exposure
to chronic variable stress reduces adult hippo
campal volume and spatial cognition [113] . While
it is readily apparent that adolescence is a sig-
nificant neurodevelopmental stage, compara-
tively little is known about the effects of stress
on brain structural and functional plasticity at
this time. Little has been reported with regard
to alterations in epigenetic phenomena. Given
the importance of the adolescent transition in
the development of human mental disorders, it
is to be hoped that this dearth of knowledge can
soon be remedied.
Neuroepigenetic effects of stress in
adult life
The hippocampus, a key brain structure for
episodic and spatial memory and also mood
regulation, is a highly stress-sensitive tissue and,
ho
as a result, it has received substantial attention
from stress, learning and memory and mood
disorder researchers. The hippocampus shows
plasticity in response to both acute and chronic
stressors, as well as antidepressant treatments,
ut
and also spatial and episodic learning tasks;
indeed, many learning and memory tasks are
stressful, and many stressors produce some
learning (e.g.,[114]). The adult hippocampus
A
also expresses as large a variety of epigenetic
enzymes as any other brain region, as a perusal
of the Allen Brain Atlas will demonstrate [115] .
Therefore, the hippocampus has proven to be
fertile ground for the study of the intersection
of stress, plasticity and epigenetics, although, as
we shall see, it is not the only brain region where
this intersection can be found.
Fear conditioning, which is by definition psy-
chologically stressful, has been of great use as
a behavioral probe of the epigenetic influences
on learning and plasticity in animal models. As
this area has been the subject of recent, system-
atic review, both in this journal and elsewhere
[116,117] , we will not attempt a comprehensive
treatment here; rather, we will focus on salient
findings with relevance to stress-induced plas-
ticity. It has long been hypothesized that DNA
future science group
Review
methylation might undergird the formation of
memory [118120] , but the involvement of this
epigenetic mark in memory was only recently
established, and the first demonstration of an
epigenetic modification playing a role in fear
conditioning regarded histone acetylation [121] .
Miller and Sweatt demonstrated that fear con-
ditioning increases the expression of DNMT3A
and 3B in the hippocampus, and that treat-
ment with DNA methyltransferase inhibitors
impaired memory consolidation [122] . Fear con-
ditioning also altered the methylation status of
the reelin, PP1 and BDNF genes [122,123] . PP1 is
of interest as it plays a role as a phosphatase at
histone H3 serine10, and this activity would
of
appear to be the basis for its role in memory
formation [124,125] . Similarly, Maddox and Schafe
have shown that HDAC inhibition in the lateral
amygdala enhances fear memory reconsolida-
ro
tion, while inhibition of DNMTs interferes with
reconsolidation [126] .
A series of studies performed in the Tsai labo-
ratory established a role for histone acetylation
in memory formation as well. Beginning with
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the observation that environmental enrichment
ameliorated memory deficits in a transgenic
mouse model of neurodegenerative disease,
these investigators explored the possibility that
these effects might be replicated by treatment
with an HDAC inhibitor, as in fact proved to
be the case as HDAC inhibition improved both
memory and synapse formation in the anterior
cingulate cortex [127] . Subsequently, the same
group showed that these effects were regulated
via the classI HDAC, HDAC2, which appears
to be the major HDAC of its class in neurons.
HDAC2 did so by regulating the expression
of a relatively small group of genes, including
a number of glutamate receptor subunits and
BDNF [128] , the latter finding replicating an ear-
lier one by Bredy etal. [129] . A significant linkage
between epigenetic chromatin modifications and
synaptic plasticity was recently established by
Calfa and collaborators, who found that inhibi-
tion of HDACs blocked the capacity of BDNF
to increase both spine density and the volume of
excitatory neurotransmitter release in the CA1
of the rat hippocampus [130] .
One of the earliest findings explicitly
implicating stress in the regulation of epigen-
etic marks in brain was that of Bilang-Bleuel
etal. who showed that an acute stress, forced
swimming, increased the dual phospho-acetyl
mark at serine 10 and lysine 14 of histone H3
(H3S10p-K14ac) in the rat dentate gyrus [131] .
The H3S10p-K14ac mark is associated with
www.futuremedicine.com 7
Review Hunter & McEwen
transcriptional activation [132,133] , and previous
work had shown it to be associated with treat-
ment with a variety of neurotransmitter agonists
[134] . Building upon this finding, the Reul group
showed that the same effect was observable
with a different stressor, and that it was NMDA
receptor-dependent and associated with neuro-
nal activation (as measured by c-fos induction)
in the same cells that showed changes in the
double mark [135,136] . Exercise, which may be
regarded as a positive stressor [54] , also increases
levels of the mark, suggesting that changes in
H3S10p-K14ac may be an adaptive, rather than
pathogenic, response to stress [137] . GABAergic
interneurons appear to be a countervailing force
on stress-induced increases in H3S10p-K14ac
[138] . Given the established synergy between the
glutamate and glucocorticoid systems in produc-
ing stress-induced plasticity [139] , it is of interest
ro
that stress-induced increases in H3S10p-K14ac
require both systems acting through the novel
intermediaries Elk-1 and MSK1. The GR inter-
acts directly with these proteins, and this inter-
action appears to promote their phosphorylation
rP
by the ERK-MAPK pathway acting downstream
of activated NMDA receptors. Furthermore,
this coinduction of the mark plays a role in the
memory of the stress that produced it [140,141] .
Social defeat stress, which is one of the better
ho
rodent models of human depression in terms of
ethological and face validity [142] , also has an
impact on the neural epigenome, as was first
demonstrated by the Nestler laboratory [143] .
They showed that chronic social defeat in adult
ut
mice significantly increased the levels of the
repressive H3K27 trimethyl mark at the BDNF
promoter, while treatment with antidepressant
drugs increased marks associated with active
A
transcription, such as H3 acetylation and H3K4
methylation [143,144] . Later studies by the same
group linked similar changes with changes in
HDAC function in the nucleus accumbens after
stress or cocaine treatment. Notably, they found
that HDAC2 had an antidepressant effect in the
defeat model [145,146] . A further link with the
epigenetic actors in learning and memory was
the discovery that defeat increased accumbal
DNMT3A expression, while chronic cocaine
reduced it, and that these changes were associ-
ated with plastic changes in dendritic spines in
the same brain region [147] . Resilience to social
stress also correlates with altered DNA meth-
ylation of the CRH gene in the paraventricular
hypothalamus [148] and levels of the repressive
H3K9 and K27 trimethylations in the accum-
bens [149,150] . Levels of histone H3K9 di- and
8 Epigenomics (2013) 5(2)
tri-methylation in the nucleus accumbens also
change in response to cocaine administration,
where this mark is also associated with changes
in dendritic spines [151] . In the hippocampus,
this mark is profoundly upregulated by acute
stress or by chronic treatment with the anti-
depressant fluoxetine [152] ; the same study also
demonstrated stress-dependent changes in both
the H3K4me3 (moderately increased in chronic
stress) and H3K27me3 (substantially reduced by
acute stress) marks in the hippocampus. Both
H3K4 and H3K27 methylation were found to
be reduced at the prodynorphin promoter in the
striatum of rats subjected to an acute swim stress
[153] . The balance of evidence from these studies
of
suggests that interventions that increase levels of
the H3K9me3 mark or inhibit HDAC2 can pro-
mote resilience to stress and depressive behavior
in animal models and, by extension, also in man.
Our finding that acute restraint stress rapidly
and globally upregulates the H3K9me3 mark in
a hippocampus-specific fashion [152] , led us to
hypothesize that this mark might be involved
in suppressing the expression of transposable
elements, which can be induced by stress [154] .
Tight control of genomic stability in terminally
differentiated neurons is of obvious importance,
and so we used chromatin immunoprecipitation
sequencing of the H3K9me3 mark to deter-
mine if in fact this mark showed a selective bias
towards accumulation at transposable elements
after acute stress. Our results showed that, while
there was little directionality to the changes in
H3K9me3 levels on genes, stress produced an
increase in the mark at more than 50-fold more
transposable elements than elements that saw a
decrease, accounting for at least 50,000 distinct
loci. This effect was accompanied by a 50% or
more decrease in the expression of retrotranspo-
son RNAs, notably the B2 SINE and IAP endog-
enous retrovirus (see Figure2 ) [155] . These results
point to an entirely novel area of investigation
in the neurobiology of the stress response, sug-
gesting that a large and hitherto underexplored
portion of the genome may be involved both in
the normal response to stress and, potentially,
in the pathogenesis of stress-related disorders.
The latter possibility has been given more weight
by the recent finding that LINE-1 and Alu ret-
rotransposons were differentially DNA methyl-
ated between veterans with PTSD and combat-
deployed controls [156] . Transposable elements
can of course contribute to genomic instability,
but they may also have significant roles in the
regulation of transcription, RNA stability and
so on [157] .
future science group
 Stress & anxiety across the lifespan: structural plasticity & epigenetic regulation Review
Relative to DNA methylation and chromatin expression of the CRHR1 receptor and, thereby,
modifications, ncRNAs have received less atten- reduces anxiety [161] . In the mouse frontal cortex,
tion with regard to stress and brain plasticity. acute stress selectively alters the expression of
Nonetheless, a number of miRNAs have been Let-7a, miR-9 and 26a/b, while it has no effect
identified that are involved in the regulation of on these miRNAs in the hippocampus [162] . Sim-
GR, including miR-124a and miR-18a [158,159] . ilarly, regionally specific effects on miR-186 and
Both acute and chronic stress regulate the expres- 709 were found in the hippocampus, prefrontal
sion of miR-134 and -183 in the hippocampus cortex and cerebellum of chronically stressed rats
and amygdala, and through them alters the [163] . Sleep deprivation stress altered the expres-
splicing of acetylcholinesterase mRNA, poten- sion of ten miRNAs in mouse brain, seven of
tially allowing for fine-tuning of the cholinergic which appear to be corticosteroid regulated
responsiveness of these regions [160] . Acute and [164] . While all of the findings reviewed above
chronic stress also modulate the expression of involve miRNA, other species of ncRNA are
miR-34 in the amygdala, where it suppresses the likely to be involved in the brains adaptation or

of
20,000

15,000
Number of islands

ro
Stress
Stress up
10,000 Stress down
rP
5000

0
ERV/LTR

Satellite
LINE

SINE

DNA

ncRNA
Simple/low
complexity/
other

ho

Hippocampus RNA
2
ut

0 Genomic Transcriptional
Fold change

instability? stability?
-2
A

-4 *

**
-6
B2 control

B2 stress

IAP control

IAP stress

L1 control

L1 stress

Figure 2. Epigenetic regulation of mobile genomic elements. (A) Displays a comparison of

transposable element loci, broken down by taxon, that showed either an increase in H3K9me3 levels
after stress (stress up) or a decrease (stress down). Retrotransposons (LINEs; ERV/TR; SINEs) and
simple repeats were enriched 50-fold or more, while satellite repeats, DNA transposons and ncRNAs
were less enriched. (B) Shows that this increase was accompanied by a hippocampus-specific
suppression of the expression of RNAs for several of the elements. Other tissues showed no such
change. These findings raise the possibility that loss of epigenetic control could contribute to
transposon-induced genomic and transcriptional instability, contributing to brain weathering.
ERV: Endogenous retrovirus; IAP: Intracisternal A particle; LINE: Long interspersed nuclear elements;
LTR: Long terminal repeat; SINE: Short interspersed nuclear element.
Adapted from [155] .

future science group www.futuremedicine.com 9

Review Hunter & McEwen
maladaptation to stress. The recent finding that
piRNAs, whose actions were long thought to be
restricted to the gonads, play an active role in
synaptic plasticity in the Aplysia [165] , raises the
question as to their involvement in mammalian
synaptic plasticity, memory and stress. Similarly,
in Arabidopsis thalania, transposable element
RNA has the capacity to regulate the plants
stress response via the siRNA pathway [166] . Our
own observations that the RNAs for a number of
transposable elements are regulated by stress in
the hippocampus, suggests that there may be a
role for these ncRNAs in the mammalian stress
response as well.
Neuroepigenetic effects of stress in
aging
Aging is associated with changes in the stress
axis, cognition and neuronal plasticity, and
ro
is regarded by some as the last epigenetically
regulated stage of development [167,168] . While
aging is generally viewed as a gradual process,
it includes more clearly demarcated endocrine
events relevant to both stress responsivity and
rP
brain plasticity, such as menopause and adreno-
pause. However, the degree to which these events
might be under epigenetic control is not yet
clear. In the aged rat, the HPA axis response to
stress is prolonged when compared with young
ho
adult animals, and GR levels decline [169,170] .
These findings by Robert Sapolsky led him to
propose the glucocorticoid cascade hypothesis
of aging in 1986 [171] , which proposes that age-
induced decline in GR feedback exposes the
ut
brain to progressively higher levels of cortico-
steroids, which, in turn, impairs hippocampus
structure and function and leads to cognitive
decline. While this hypothesis has been modi-
A
fied to de-emphasize neuronal loss and empha-
size age-related loss of structural and functional
plasticity [172] , it is evident that stress and HPA
activity have a role in vulnerability to brain aging
in both humans and animals [1,173] . As is readily
apparent, aging is often associated with cognitive
decline, and some of this decline with reduced
plasticity. In plastic, stress-sensitive regions, such
as the hippocampus, aging is associated with
reductions in synapse number, neurogenesis
and long-term potentiation, accompanied by an
increase in long-term depression after an acute
stressor [174176] . In the aged rat prefrontal cortex,
chronic stress retains the capacity to reduce den-
dritic complexity, but the region appears to have
lost the resilience present in young adults and
does not recover to prestress levels of structural
complexity [12] . How stress and epigenetics are
10 Epigenomics (2013) 5(2)
involved in the aging process is only beginning
to be understood.
It is evident that aging is associated with
changes in the epigenome; indeed, a global com-
parison of methylated DNA between human
newborns, young adults and centenarians found
that extreme old age was associated with a sub-
stantial decline in overall DNA methylation in
lymphocytes [177] . In the brain, however, DNA
methylation increases with age, as is evident in
some animal models and human studies [178181] .
Furthermore, evidence is emerging that some dis-
orders of aging, such as Alzheimers disease, may
be associated with even greater increases in levels
of methylated DNA in the brain [182] . DNMT3a
of
expression in the hippocampus increases with
age and, interestingly, caloric restriction, which
is thought to promote healthy aging [183] , reduces
this increase [184] . As caloric restriction tends to
increase circulating corticosteroids [185] , this study
raises interesting questions about how a life his-
tory of stress might alter the DNA methylation
profile in the aging brain, although it is worth not-
ing that corticosteroids can have positive effects
on plasticity and that stress-mediated changes
involve other molecules, such as glutamate [186] .
On the other hand, another recent study found
reduced levels of DNMT3a in aged mouse brain
and showed that increasing the levels of the 3a2
version improves cognition. This is an issue that
will have to be resolved with further experimenta-
tion, with particular attention paid to the stress
history of the animals. As has been well estab-
lished, here and elsewhere, different stress his-
tories can produce widely divergent outcomes in
brain and behavior. Brain DNA hydroxymethyl-
ation also appears to increase with age and due to
its poorer interaction with DNA methyl-binding
proteins is likely to interfere with their function
[187,188] , and, by extension, cognition.
Several groups have found that aging and
neurodegeneration is associated with increased
HDAC2 expression in the hippocampus and
reduced acetylation at the H3K9 and H4K12
loci, and that age-related cognitive deficits could
be reversed with enhanced BDNF signaling,
HDAC inhibitors or shRNA directed against
HDAC2 [189191] . Most salient in terms of the
present discussion is the finding that the increase
in HDAC2 expression in the neurodegenerat-
ing brain is driven by the binding of GR to the
HDAC promoter, clearly linking the stress axis
with what is, at present, the best understood epi-
genetic mediator of age-related cognitive decline
[189] . In contradistinction to these findings, other
groups have found that histone H4 acetylation
future science group
 Stress & anxiety across the lifespan: structural plasticity & epigenetic regulation
and H3K9 trimethylation increase with age in
mouse hippocampal and cortical neurons, and
these increases are greater in neurons from the
3xTg transgenic model of Alzheimers disease [192] ,
and the increase in H3K9me3 was associated with
decreased BDNF expression. Of course, a global
increase in histone H4 acetylation is likely sepa-
rable from a decrease in the acetylation of one of
many basic amino acid residues in the H4 tail.
Indeed, there is some evidence that the true pic-
ture may be more complex than either of these
narratives would suggest. Castellano recently
demonstrated that the subregional hippocampal
epigenetic profile of spatial learning in age unim-
paired rats is largely indistinguishable from young
rats with the exception of an increase in global
H4 acetylation, which was associated with age in
both impaired and unimpaired animals. What
differed in age-impaired animals was an inabil-
ity to reduce HDAC2 expression in response to
behavioral activation [193] , and a lack of coor-
dination of epigenetic changes with memory
performance. Another important finding of the
latter study was that several commercial antibod-
ies against specific histone modifications lacked
the advertised specificity, which is worth noting,
both in evaluating the literature to date, and in
designing future studies in the field of neuroepi-
genetics. While we now have the basic lineaments
ho
of an understanding of some of the interactions
between the stress axis and epigenetic and syn-
aptic plasticity in the brain, it should be evident
that much further work is to be done before our
understanding of the impact of stress during this
ut
final life stage is fully understood.
Conclusion
While the interactions between external stressors,
A
epigenetics and brain plasticity across the lifes-
pan have only begun to be explored, it is read-
ily apparent that this area of exploration is offer-
ing insights into how the environment produces
persistent changes in the brain and behavior. Of
greater interest from the translational perspective
is the fact that many of these changes appear to be
reversible via structured environmental interven-
tions or pharmacologic means.
A problem for the study of epigenetics in the
brain is the transient nature of many of the phe-
nomena coupled with the necessity for making
exvivo observations. As we have argued through-
out, stress has significant effects on the epigenome,
and thus attention to stress history, reducing the
stress of sacrificing experimental animals and rapid
tissue dissection are very important considerations.
It is not evident that these concerns are always
future science group
Review
foremost in the minds of neuroepigeneticists, and
as a result a certain amount of confusion in the
literature is likely to occur. We would suggest that
controlling for stress is of substantial importance
for the fields rapid advancement.
Future work in the area will have to go further
in describing the mechanisms by which epigenetic
changes persist and explain their regional selectiv-
ity. In the latter case, increasing the level of ana-
tomical detail involved in neuroepigenetic analysis
will be crucial. Technical advances in next-gener-
ation sequencing will drive some of this, as will
techniques for the analysis of specific cell types,
such as bacterial artificial chromosome-translating
ribosome affinity purification [194,195] or circuit-
of
based analyses using optogenetics, as will more
established approaches.
As we have pointed out above, the adolescent
period, in spite of its obvious importance as a
ro
period of increased susceptibility to a variety of
stress-related mental disorders [196], has had little to
no examination of the impact of stress on epigen-
etic marks in the brain. Nor has much attention
been paid, as yet, to how stress-induced epigenetic
rP
changes at one life stage, such as infancy, might
interact with stress, and susceptibility to stress in
later life stages, such as adolescence or aging.
Much of the research to date on the neuro
epigenetics of stress has logically focused on well-
known genes, for example, GR and BDNF. It is
likely, however, that these are not the only genomic
elements involved in the epigenetics of stress and
anxiety. As an example, the mineralocorticoid
receptor, which plays a significant role in HPA axis
feedback and anxiety [197] , has yet to be examined
for epigenetic activity in the brain, although it has
been associated with altered histone methylation
in the kidney [198] . The availability of cheaper and
deeper next-generation sequencing technologies
will be of great help in broadening the number of
potential genomic elements examined to encom-
pass more than the genes themselves to the other
95% of the genome, most of which may be actively
transcribed [199] , although their functions remain
largely unexamined.
For basic discoveries about the epigenetics
of stress and anxiety to leave the bench and be
translated to the bedside, epigenetic pharmacol-
ogy must advance substantially. While many his-
tone deacetylase inhibitors have been approved for
human use, drugs to inhibit or increase histone
methylation are relatively few and far between,
although some methyltransferase inhibitors are
becoming available for research purposes [200,201] .
As to the many other histone modifications or
ncRNA, still less is known.
www.futuremedicine.com 11
Review Hunter & McEwen

Future perspective hoped that as our fundamental understanding of

The field of the epigenetics of stress and anxi-
ety has many open questions outstanding.
Notably, how epigenetic activity integrates with
better described systems such as neurotransmit-
ters. Another question is how stable epigenetic
changes are maintained, as recent research has
revealed that many, if not most, epigenetic marks
are much less stable and far more dynamic than
had been thought. One of the greatest open
questions is the issue of specificity in neuro-
epigenetics. This is significant at a number of
levels. At the level of experimental tools there
are few truly specific pharmacophores and
genetic manipulations of epigenetic informa-
chromatin structure, transcription and the vast
terra incognita of what used to be called Junk
DNA improves, so will our understanding of
the specificity of neuroepigenomic phenomena.
Epigenetic mechanisms are an extremely
promising means by which to understand how
the slings and arrows of both ordinary and
extraordinary misfortune affect how our brain
functions across our lifespan, and how some indi-
viduals and certain times of life might be more
vulnerable to the development of particular brain
disorders. As our technical and observational
capacity improves, it seems likely that we will
gain a much more profound understanding of

tion; although quite useful when well employed,
they can substantially muddy our understanding
when they are not. The question of how a rela-
tively nonspecific HDAC inhibitor, for example,
of
how stress in our environment produces lasting
changes in our brains, mood and behavior.
Financial & competing interests disclosure

ro
alters the expression of only a small fraction of
genes in a small number of brain regions, as has
been observed by a number of groups, is also
highly significant. One could imagine that the
combination of chromatin status, and the bind-
rP
ing of various elements of the transcriptional
machinery, could regulate the accessibility of
certain genes to manipulation, but this hypoth-
esis has not yet been tested in the brain. It is to be
ho
RG Hunter and BS McEwen thank NIH MH41256 and
the Help for Depression Research Foundation (HDRF) for
their support. The authors have no other relevant affilia-
tions or financial involvement with any organization or
entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript
apart from those disclosed.
No writing assistance was utilized in the production of
this manuscript.

Executive summary
Background
Stress has a significant effect on the health of a variety of bodily systems.
ut

Stress effects brain plasticity at a variety of levels.

Stress, particularly chronic and early-life stress, can have long-lasting effects on the brain and behavior.
Sex has a profound influence on stress responsivity and brain plasticity.
Neuroepigenetic effects of stress in early life
A

Early-life stress is well established to have lasting impacts on health in both humans and animal models.
The effects of stressful life experience can be transmitted epigenetically from parents to offspring across multiple generations.
Both pre- and post-natal stress can alter the expression of a variety of epigenetic marks in the brain, with significant consequences for
gene expression and brain function.
Adolescence is one of the most poorly understood periods with regard to the effects of stress on brain plasticity, yet it is likely to be
one of the most important to our understanding of human mental disorders.
Neuroepigenetic effects of stress in adult life
Stress in adult life is well known to influence health and disease.
The brain, particularly regions such as the hippocampus, is sensitive to stress in adult life, as in early life, although the impacts can be
different.
Adult stressors and stressful learning paradigms have been shown to alter a number of different epigenetic pathways in the brain.
Recent studies suggest that stress interacting with epigenetic mechanisms may alter the behavior of transposable elements in the
genome of the hippocampus.
Neuroepigenetic effects of stress in aging
The aging brain is less resilient to stress than during earlier life stages; thus, stress can have a more persistent negative impact on brain
structure and function during aging.
There are epigenetic correlates of aging in the brain, and some of these have shown alteration with stress.

12 Epigenomics (2013) 5(2) future science group

 Stress & anxiety across the lifespan: structural plasticity & epigenetic regulation
References
Papers of special note have been highlighted as:
n of interest
nn of considerable interest
1 Lupien SJ, McEwen BS, Gunnar MR,
HeimC. Effects of stress throughout the
lifespan on the brain, behaviour and
cognition. Nat. Rev. Neurosci. 10(6), 434445
(2009).
2 McEwen BS, Gianaros PJ. Central role of the
brain in stress and adaptation: links to
socioeconomic status, health, and disease.
Ann. NY Acad. Sci. 1186, 190222 (2010).
3 McEwen BS, Eiland L, Hunter RG,
MillerMM. Stress and anxiety: structural
plasticity and epigenetic regulation as a
consequence of stress. Neuropharmacology
62(1), 312 (2012).
4 McEwen BS. Stress, sex, and neural
adaptation to a changing environment:
mechanisms of neuronal remodeling. Ann. NY
Acad. Sci. 1204(Suppl.), E38E59 (2010).
5 Bennett E, Diamond M, Krech D,
Rosenzweig M. Chemical and anatomical
plasticity of brain. Science 146, 610619
(1964).
6 Erickson KI, Voss MW, Prakash RS etal.
Exercise training increases size of
hippocampus and improves memory. Proc.
Natl Acad. Sci. USA 108(7), 30173022
(2011).
ho
7 Wang X, Merzenich MM, Sameshima K,
Jenkins WM. Remodelling of hand
representation in adult cortex determined by
timing of tactile stimulation. Nature 378,
7175 (1995).
8 Draganski B, Gaser C, Kempermann G etal.
ut
Temporal and spatial dynamics of brain
structure changes during extensive learning.
J.Neurosci. 26(23), 63146317 (2006).
9 Bezzola L, Merillat S, Gaser C, Jancke L.
A
Training-induced neural plasticity in golf
novices. J.Neurosci. 31(35), 1244412448
(2011).
10 McEwen BS. Physiology and neurobiology of
stress and adaptation: central role of the
brain. Physiol. Rev. 87, 873904 (2007).
11 McEwen BS. Stress and hippocampal
plasticity. Annu. Rev. Neurosci. 22, 105122
(1999).
12 Bloss EB, Janssen WG, McEwen BS,
Morrison JH. Interactive effects of stress and
aging on structural plasticity in the prefrontal
cortex. J.Neurosci. 30(19), 67266731
(2010).
13 Vyas A, Mitra R, Rao BSS, Chattarji S.
Chronic stress induces contrasting patterns of
dendritic remodeling in hippocampal and
amygdaloid neurons. J.Neurosci. 22,
68106818 (2002).
future science group
14 Roozendaal B, McEwen BS, Chattarji S.
Stress, memory and the amygdala. Nat. Rev.
Neurosci. 10, 423433 (2009).
15 McEwen BS, Gianaros PJ. Stress- and
allostasis-induced brain plasticity. Annu. Rev.
Med. 62, 431445 (2011).
16 Pruessner JC, Baldwin MW, Dedovic K etal.
Self-esteem, locus of control, hippocampal
volume, and cortisol regulation in young and
old adulthood. NeuroImage 28, 815826
(2005).
17 Gurvits TV, Shenton ME, Hokama H etal.
Magnetic resonance imaging study of
hippocampal volume in chronic, combat-
related posttraumatic stress disorder. Biol.
Psychiatry 40, 10911099 (1996).
18 Cho K. Chronic jet lag produces temporal
of
lobe atrophy and spatial cognitive deficits.
Nat. Neurosci. 4, 567568 (2001).
19 Davidson RJ, McEwen BS. Social influences
on neuroplasticity: stress and interventions to
ro
promote well-being. Nat. Neurosci. 15(5),
689695 (2012).
20 Holzel BK, Carmody J, Evans KC etal. Stress
reduction correlates with structural changes
in the amygdala. Soc. Cogn. Affect. Neurosci.
rP
5(1), 1117 (2009).
21 Stahl SM. Psychotherapy as an epigenetic
drug: psychiatric therapeutics target
symptoms linked to malfunctioning brain
circuits with psychotherapy as well as with
drugs. J.Clin. Pharm. Ther. 37(3), 249253
(2012).
22 McEwen BS. Protective and damaging effects
of stress mediators. N.Engl. J.Med. 338,
171179 (1998).
23 Nugent BM, McCarthy MM. Epigenetic
underpinnings of developmental sex
differences in the brain. Neuroendocrinology
93(3), 150158 (2011).
24 Hoffmann A, Spengler D. The lasting legacy
of social stress on the epigenome of the
hypothalamicpituitaryadrenal axis. 38 Danese A, McEwen BS. Adverse childhood
Epigenomics 4(4), 431444 (2012).
25 Bale TL. Sex differences in prenatal
epigenetic programming of stress pathways.
Stress 14(4), 348356 (2011).
26 Maccari S, Morley-Fletcher S. Effects of
prenatal restraint stress on the hypothalamus
pituitaryadrenal axis and related behavioural
and neurobiological alterations.
Psychoneuroendocrinology 32, S10S15 (2007).
27 Francis DD, Diorio J, Plotsky PM, Meaney
MJ. Environmental enrichment reverses the
effects of maternal separation on stress
reactivity. J.Neurosci. 22, 78407843 (2002).
28 Plotsky PM, Thrivikraman KV, Nemeroff
CB, Caldji C, Sharma S, Meaney MJ. Long-
term consequences of neonatal rearing on
central corticotropin-releasing factor systems
www.futuremedicine.com
Review
in adult male rat offspring.
Neuropsychopharmacology 30, 21922204
(2005).
29 Eiland L, McEwen BS. Early life stress followed
by subsequent adult chronic stress potentiates
anxiety and blunts hippocampal structural
remodeling. Hippocampus 22(1), 8291 (2012).
30 Caldji C, Diorio J, Meaney MJ. Variations in
maternal care in infancy regulate the
development of stress reactivity. Biol. Psychiat.
48, 11641174 (2000).
31 Akers KG, Yang Z, Delvecchio DP etal. Social
competitiveness and plasticity of
neuroendocrine function in old age: influence
of neonatal novelty exposure and maternal care
reliability. PLoS ONE 3(7), e2840 (2008).
32 Tang AC, Reeb-Sutherland BC, Yang Z,
Romeo RD, McEwen BS. Neonatal novelty-
induced persistent enhancement in offspring
spatial memory and the modulatory role of
maternal self-stress regulation. J.Neurosci.
31(14), 53485352 (2011).
33 Francis D, Diorio J, Liu D, Meaney MJ.
Nongenomic transmission across generations of
maternal behavior and stress responses in the
rat. Science 286, 11551158 (1999).
34 Weaver ICG, Cervoni N, Champagne FA etal.
Epigenetic programming by maternal behavior.
Nat. Neurosci. 7, 847854 (2004).
35 Kaufman D, Smith ELP, Gohil BC etal. Early
appearance of the metabolic syndrome in
socially reared bonnet macaques. J.Clin.
Endocrinol. Metab. 90, 404408 (2005).
36 Kaufman D, Banerji MA, Shorman I etal.
Early-life stress and the development of obesity
and insulin resistance in juvenile bonnet
macaques. Diabetes 56, 15 (2007).
37 Mcgowan PO, Sasaki A, Dalessio AC etal.
Epigenetic regulation of the glucocorticoid
receptor in human brain associates with
childhood abuse. Nat. Neurosci. 12, 241243
(2009).
experiences, allostasis, allostatic load, and age-
related disease. Physiol. Behav. 106(1), 2939
(2012).
39 Entringer S, Epel ES, Kumsta R etal. Stress
exposure in intrauterine life is associated with
shorter telomere length in young adulthood.
Proc. Natl Acad. Sci. USA 108(33), E513E518
(2011).
40 Shonkoff JP, Boyce WT, McEwen BS.
Neuroscience, molecular biology, and the
childhood roots of health disparities. JAMA
301, 22522259 (2009).
41 Anda RF, Butchart A, Felitti VJ, Brown DW.
Building a framework for global surveillance of
the public health implications of adverse
childhood experiences. Am. J.Prev. Med.
39(1), 9398 (2010).
13
Review Hunter & McEwen
42 Evans GW, Gonnella C, Marcynyszyn LA,
Gentile L, Salpekar N. The role of chaos in
poverty and childrens socioemotional
adjustment. Psychol. Sci. 16, 560565 (2004).
43 Lupien SJ, Parent S, Evans AC etal. Larger
amygdala but no change in hippocampal
volume in 10-year-old children exposed to
maternal depressive symptomatology since
birth. Proc. Natl Acad. Sci. USA 108(34),
1432414329 (2011).
44 Farah MJ, Shera DM, Savage JH etal.
Childhood poverty: Specific associations with
neurocognitive development. Brain Res. 1110,
166174 (2006).
45 Danese A, McEwen BS. Adverse childhood
experiences, allostasis, allostatic load, and
age-related disease. Physiol. Behav. 106(1),
2939 (2011).
46 Hart B, Risley TR. Meaningful Differences in
the Everyday Experience of Young American
Children. Brookes Publishing Company, MD,
USA (1995).
47 Pesonen AK, Raikkonen K. The lifespan
consequences of early life stress. Physiol.
Behav. 106(5), 722727 (2012).
48 Roseboom TJ, Painter RC, van Abeelen AF,
Veenendaal MV, De Rooij SR. Hungry in the
womb: what are the consequences? Lessons
from the Dutch famine. Maturitas 70(2),
141145 (2011).
49 Heijmans BT, Tobi EW, Stein AD etal.
Persistent epigenetic differences associated
ho
with prenatal exposure to famine in humans.
Proc. Natl Acad. Sci. USA 105(44),
1704617049 (2008).
50 Yehuda R, Bell A, Bierer LM, Schmeidler J.
Maternal, not paternal, PTSD is related to
ut
increased risk for PTSD in offspring of
Holocaust survivors. J.Psychiatr. Res. 42(13),
11041111 (2008).
51 Yehuda R, Bierer LM. Transgenerational
transmission of cortisol and PTSD risk. Prog.
A
Brain Res. 167, 121135 (2008).
52 Francis DD, Meaney MJ. Maternal care and
the development of stress responses. Curr.
Opin. Neurobiol. 9(1), 128134 (1999).
53 Wosiski-Kuhn M, Stranahan AM. Opposing
effects of positive and negative stress on
hippocampal plasticity over the lifespan.
Ageing Res. Rev. 11(3), 399403 (2012).
54 Wosiski-Kuhn M, Stranahan AM. Opposing
effects of positive and negative stress on
hippocampal plasticity over the lifespan.
Ageing Res. Rev. 11(3), 399403 (2011).
55 Koenig JI, Walker CD, Romeo RD, Lupien
SJ. Effects of stress across the lifespan. Stress
14(5), 475480 (2011).
56 Vallee M, Maccari S, Dellu F, Simon H, Le
Moal M, Mayo W. Long-term effects of
prenatal stress and postnatal handling on
14
age-related glucocorticoid secretion and
cognitive performance: a longitudinal study
in the rat. Eur. J.Neurosci. 11(8), 29062916
(1999).
57 Vallee M, Mayo W, Dellu F, Le Moal M,
Simon H, Maccari S. Prenatal stress induces
high anxiety and postnatal handling induces
low anxiety in adult offspring: correlation
with stress-induced corticosterone secretion.
J.Neurosci. 17(7), 26262636 (1997).
58 Seckl JR. Glucocorticoids, developmental
programming and the risk of affective
dysfunction. Prog. Brain Res. 167, 1734
(2008).
59 Cratty MS, Ward HE, Johnson EA, Azzaro
AJ, Birkle DL. Prenatal stress increases
corticotropin-releasing factor (CRF) content
and release in rat amygdala minces. Brain Res.
675(12), 297302 (1995).
60 Murmu MS, Salomon S, Biala Y, Weinstock
M, Braun K, Bock J. Changes of spine density
ro
and dendritic complexity in the prefrontal
cortex in offspring of mothers exposed to
stress during pregnancy. Eur. J.Neurosci.
24(5), 14771487 (2006).
61 Lemaire V, Koehl M, Le Moal M, Abrous
rP
DN. Prenatal stress produces learning deficits
associated with an inhibition of neurogenesis
in the hippocampus. Proc. Natl Acad. Sci.
USA 97(20), 1103211037 (2000).
62 Coe CL, Kramer M, Czeh B etal. Prenatal
stress diminishes neurogenesis in the dentate
gyrus of juvenile rhesus monkeys. Biol.
Psychiatry 54(10), 10251034 (2003).
63 Fujioka T, Sakata Y, Yamaguchi K, Shibasaki
T, Kato H, Nakamura S. The effects of
prenatal stress on the development of
hypothalamic paraventricular neurons in fetal
rats. Neuroscience 92(3), 10791088 (1999).
64 Fujioka A, Fujioka T, Ishida Y, Maekawa T,
Nakamura S. Differential effects of prenatal
stress on the morphological maturation of
hippocampal neurons. Neuroscience 141(2),
907915 (2006).
65 Fujioka T, Fujioka A, Tan N etal. Mild
prenatal stress enhances learning performance
in the non-adopted rat offspring. Neuroscience
103(2), 301307 (2001).
66 Mueller BR, Bale TL. Sex-specific
programming of offspring emotionality after
stress early in pregnancy. J.Neurosci. 28(36),
90559065 (2008).
67 Morgan CP, Bale TL. Early prenatal stress
epigenetically programs dysmasculinization
in second-generation offspring via the
paternal lineage. J.Neurosci. 31(33),
1174811755 (2011).
68 Oberlander TF, Weinberg J, Papsdorf M,
Grunau R, Misri S, Devlin AM. Prenatal
exposure to maternal depression, neonatal
methylation of human glucocorticoid receptor
Epigenomics (2013) 5(2)
gene (NR3C1) and infant cortisol stress
responses. Epigenetics 3(2), 97106 (2008).
69 Jensen Pena C, Monk C, Champagne FA.
Epigenetic effects of prenatal stress on 11beta-
hydroxysteroid dehydrogenase-2 in the
placenta and fetal brain. PLoS ONE 7(6),
e39791 (2012).
70 Marsit CJ, Maccani MA, Padbury JF,
LesterBM. Placental 11-beta hydroxysteroid
dehydrogenase methylation is associated with
newborn growth and a measure of
neurobehavioral outcome. PLoS ONE 7(3),
e33794 (2012).
71 Matrisciano F, Tueting P, Dalal I etal.
Epigenetic modifications of GABAergic
interneurons are associated with the
schizophrenia-like phenotype induced by
of
prenatal stress in mice. Neuropharmacology
doi:http://dx.doi.org/10.1016/j.
bbr.2011.03.031 (2012) (Epub ahead of
print).
72 Brown AS. The environment and
susceptibility to schizophrenia. Prog.
Neurobiol. 93(1), 2358 (2011).
73 Koenig JI, Kirkpatrick B, Lee P.
Glucocorticoid hormones and early brain
development in schizophrenia.
Neuropsychopharmacology 27(2), 309318
(2002).
74 Lemaire V, Lamarque S, Le Moal M, Piazza
PV, Abrous DN. Postnatal stimulation of the
pups counteracts prenatal stress-induced
deficits in hippocampal neurogenesis. Biol.
Psychiatry 59(9), 786792 (2006).
75 Dicorcia JA, Tronick E. Quotidian resilience:
exploring mechanisms that drive resilience
from a perspective of everyday stress and
coping. Neurosci. Biobehav. Rev. 35(7),
15931602 (2011).
76 Francis D, Diorio J, Liu D, Meaney MJ.
Nongenomic transmission across generations
of maternal behavior and stress responses in
the rat. Science 286(5442), 11551158
(1999).
77 Champagne FA, Francis DD, Mar A, Meaney
MJ. Variations in maternal care in the rat as a
mediating influence for the effects of
environment on development. Physiol. Behav.
79(3), 359371 (2003).
78 Liu D, Diorio J, Tannenbaum B etal.
Maternal care, hippocampal glucocorticoid
receptors, and hypothalamic-pituitary-
adrenal responses to stress. Science 277(5332),
16591662 (1997).
79 Champagne DL, Bagot RC, Van Hasselt F
etal. Maternal care and hippocampal
plasticity. evidence for experience-dependent
structural plasticity, altered synaptic
functioning, and differential responsiveness
to glucocorticoids and stress. J.Neurosci.
28(23), 60376045 (2008).
future science group
 Stress & anxiety across the lifespan: structural plasticity & epigenetic regulation
80 Bagot RC, van Hasselt FN, Champagne DL,
Meaney MJ, Krugers HJ, Joels M. Maternal
care determines rapid effects of stress
mediators on synaptic plasticity in adult rat
hippocampal dentate gyrus. Neurobiol Learn.
Mem. 92(3), 292300 (2009).
81 Del Giudice M, Ellis BJ, Shirtcliff EA. The
Adaptive Calibration Model of stress
responsivity. Neurosci. Biobehav. Rev. 35(7),
15621592 (2012).
82 Weaver IC, Cervoni N, Champagne FA etal.
Epigenetic programming by maternal behavior.
Nat. Neurosci. 7(8), 847854 (2004).
83 Cervoni N, Szyf M. Demethylase activity is
directed by histone acetylation. J.Biol. Chem.
276(44), 4077840787 (2001).
84 Weaver IC, Dalessio AC, Brown SE etal. The
transcription factor nerve growth factor-
inducible protein a mediates epigenetic
programming: altering epigenetic marks by
immediate-early genes. J.Neurosci. 27(7),
17561768 (2007).
85 Turner JD, Muller CP. Structure of the
glucocorticoid receptor (NR3C1) gene 5
untranslated region: identification, and tissue
distribution of multiple new human exon 1.
J.Mol. Endocrinol. 35(2), 283292 (2005).
86 Mcgowan PO, Sasaki A, Dalessio AC etal.
Epigenetic regulation of the glucocorticoid
receptor in human brain associates with
childhood abuse. Nat. Neurosci. 12(3),
342348 (2009).
ho
87 Labonte B, Yerko V, Gross J etal. Differential
glucocorticoid receptor exon 1(b), 1(c), and
1(h) expression and methylation in suicide
completers with a history of childhood abuse.
Biol. Psychiatry 72(1), 4148 (2012).
ut
88 Alt SR, Turner JD, Klok MD etal. Differential
expression of glucocorticoid receptor
transcripts in major depressive disorder is not
epigenetically programmed.
Psychoneuroendocrinology 35(4), 544556
A
(2010).
89 Tyrka AR, Price LH, Marsit C, Walters OC,
Carpenter LL. Childhood adversity and
epigenetic modulation of the leukocyte
glucocorticoid receptor: preliminary findings
in healthy adults. PLoS ONE 7(1), e30148
(2012).
90 Labonte B, Suderman M, Maussion G etal.
Genome-wide epigenetic regulation by early-
life traumagenome epigenetic regulation by
early-life trauma. Arch. Gen. Psychiatry 69(7),
722731 (2012).
91 Crudo A, Petropoulos S, Moisiadis VG etal.
Prenatal synthetic glucocorticoid treatment
changes DNA methylation States in male
organ systems: multigenerational effects.
Endocrinology 153(7), 32693283 (2012).
92 Crews D, Gillette R, Scarpino SV, Manikkam
M, Savenkova MI, Skinner MK. Epigenetic
future science group
transgenerational inheritance of altered stress
responses. Proc. Natl Acad. Sci. USA 109(23),
91439148 (2012).
93 Skinner MK, Anway MD, Savenkova MI,
Gore AC, Crews D. Transgenerational
epigenetic programming of the brain
transcriptome and anxiety behavior. PLoS
ONE 3(11), e3745 (2008).
94 Guerrero-Bosagna C, Settles M, Lucker B,
Skinner MK. Epigenetic transgenerational
actions of vinclozolin on promoter regions of
the sperm epigenome. PLoS ONE 5(9),
e13100 (2010).
95 Dietz DM, Laplant Q, Watts EL etal.
Paternal transmission of stress-induced
pathologies. Biol. Psychiatry 70(5), 408414
(2011).
of
96 Walker AK, Hawkins G, Sominsky L,
Hodgson DM. Transgenerational
transmission of anxiety induced by neonatal
exposure to lipopolysaccharide: Implications
ro
for male and female germ lines.
Psychoneuroendocrinology 37(8), 13201335
(2012).
97 Franklin TB, Russig H, Weiss IC etal.
Epigenetic transmission of the impact of early
rP
stress across generations. Biol. Psychiatry
68(5), 408415 (2010).
98 Liu D, Diorio J, Day JC, Francis DD, Meaney
MJ. Maternal care, hippocampal
synaptogenesis and cognitive development in
rats. Nat. Neurosci. 3(8), 799806 (2000).
99 Eiland L, Ramroop J, Hill MN, Manley J,
McEwen BS. Chronic juvenile stress produces
corticolimbic dendritic architectural
remodeling and modulates emotional behavior
in male and female rats.
Psychoneuroendocrinology 37(1), 3947 (2011).
100 Liu D, Caldji C, Sharma S, Plotsky PM,
Meaney MJ. Influence of neonatal rearing
conditions on stress-induced
adrenocorticotropin responses and
norepinepherine release in the hypothalamic
paraventricular nucleus. J.Neuroendocrinol.
12(1), 512 (2000).
101 Murgatroyd C, Patchev AV, Wu Y etal.
Dynamic DNA methylation programs
persistent adverse effects of early-life stress.
Nat. Neurosci. 12(12), 15591566 (2009).
102 Kriaucionis S, Bird A. DNA methylation and
Rett syndrome. Hum. Mol. Genet.
12(Suppl.2), R221R227 (2003).
103 Martinowich K, Hattori D, Wu H etal. DNA
methylation-related chromatin remodeling in
activity-dependent BDNF gene regulation.
Science 302(5646), 890893 (2003).
104 Chen WG, Chang Q, Lin Y etal.
Derepression of BDNF transcription involves
calcium-dependent phosphorylation of
MeCP2. Science 302(5646), 885889 (2003).
www.futuremedicine.com
Review
105 Roth TL, Lubin FD, Funk AJ, Sweatt JD.
Lasting epigenetic influence of early-life
adversity on the BDNF gene. Biol. Psychiatry
65(9), 760769 (2009).
106 Simmons RK, Howard JL, Simpson DN, Akil
H, Clinton SM. DNA methylation in the
developing hippocampus and amygdala of
anxiety-prone versus risk-taking rats. Dev.
Neurosci. 34(1), 5867 (2012).
107 Sturman DA, Moghaddam B. The
neurobiology of adolescence: changes in brain
architecture, functional dynamics, and
behavioral tendencies. Neurosci. Biobehav. Rev.
35(8), 17041712 (2011).
108 Mcgorry PD, Purcell R, Goldstone S,
Amminger GP. Age of onset and timing of
treatment for mental and substance use
disorders: implications for preventive
intervention strategies and models of care.
Curr. Opin. Psychiatry 24(4), 301306 (2011).
109 Blakemore SJ. Development of the social brain
in adolescence. J.R.Soc. Med. 105(3), 111116
(2012).
110 Gunnar MR, Wewerka S, Frenn K, Long JD,
Griggs C. Developmental changes in
hypothalamus-pituitary-adrenal activity over
the transition to adolescence: normative
changes and associations with puberty. Dev.
Psychopathol. 21(1), 6985 (2009).
111 Romeo RD, Karatsoreos IN, McEwen BS.
Pubertal maturation and time of day
differentially affect behavioral and
neuroendocrine responses following an acute
stressor. Horm. Behav. 50(3), 463468
(2006).
112 Romeo RD, Bellani R, Karatsoreos IN etal.
Stress history and pubertal development
interact to shape hypothalamic-pituitary-
adrenal axis plasticity. Endocrinology 147(4),
16641674 (2006).
113 Isgor C, Kabbaj M, Akil H, Watson SJ.
Delayed effects of chronic variable stress
during peripubertal-juvenile period on
hippocampal morphology and on cognitive
and stress axis functions in rats. Hippocampus
14(5), 636648 (2004).
114 Trollope AF, Gutierrez-Mecinas M, Mifsud
KR, Collins A, Saunderson EA, Reul JM.
Stress, epigenetic control of gene expression
and memory formation. Exp. Neurol. 233(1),
311 (2012).
115 Lein ES, Hawrylycz MJ, Ao N etal. Genome-
wide atlas of gene expression in the adult
mouse brain. Nature 445(7124), 168176
(2007).
116 Zovkic IB, Sweatt JD. Epigenetic Mechanisms
in learned fear: implications for PTSD.
Neuropsychopharmacology 38(1), 7793 (2012).
117 Sultan FA, Day JJ. Epigenetic mechanisms in
memory and synaptic function. Epigenomics
3(2), 157181 (2011).
15
Review Hunter & McEwen
118 Griffith JS, Mahler HR. DNA ticketing
theory of memory. Nature 223(5206),
580582 (1969).
119 Crick F. Memory and molecular turnover.
Nature 312(5990), 101 (1984).
120 Holliday R. Is there an epigenetic component
in long-term memory? J.Theor. Biol. 200(3),
339341 (1999).
121 Levenson JM, Oriordan KJ, Brown KD,
Trinh MA, Molfese DL, Sweatt JD.
Regulation of histone acetylation during
memory formation in the hippocampus.
J.Biol. Chem. 279(39), 4054540559
(2004).
122 Miller CA, Sweatt JD. Covalent modification
of DNA regulates memory formation. Neuron
53(6), 857869 (2007).
123 Lubin FD, Roth TL, Sweatt JD. Epigenetic
regulation of BDNF gene transcription in the
consolidation of fear memory. J.Neurosci.
28(42), 1057610586 (2008).
124 Koshibu K, Graff J, Beullens M etal. Protein
phosphatase 1 regulates the histone code for
long-term memory. J.Neurosci. 29(41),
1307913089 (2009).
125 Koshibu K, Graff J, Mansuy IM. Nuclear
protein phosphatase-1: an epigenetic regulator
of fear memory and amygdala long-term
potentiation. Neuroscience 173, 3036 (2011).
126 Maddox SA, Schafe GE. Epigenetic
alterations in the lateral amygdala are
ho
required for reconsolidation of a Pavlovian
fear memory. Learn. Mem. 18(9), 579593
(2011).
127 Fischer A, Sananbenesi F, Wang X,
DobbinM, Tsai LH. Recovery of learning
and memory is associated with chromatin
ut
remodelling. Nature 447(7141), 178182
(2007).
128 Guan JS, Haggarty SJ, Giacometti E etal.
HDAC2 negatively regulates memory
A
formation and synaptic plasticity. Nature
459(7243), 5560 (2009).
129 Bredy TW, Wu H, Crego C, Zellhoefer J,
Sun YE, Barad M. Histone modifications
around individual BDNF gene promoters in
prefrontal cortex are associated with
extinction of conditioned fear. Learn. Mem.
14(4), 268276 (2007).
130 Calfa G, Chapleau CA, Campbell S etal.
HDAC activity is required for BDNF to
increase quantal neurotransmitter release and
dendritic spine density in CA1 pyramidal
neurons. Hippocampus 22(7), 14931500
(2011).
131 Bilang-Bleuel A, Ulbricht S, Chandramohan
Y, De Carli S, Droste SK, Reul JM.
Psychological stress increases histone H3
phosphorylation in adult dentate gyrus
granule neurons: involvement in a
16
glucocorticoid receptor-dependent
behavioural response. Eur. J.Neurosci. 22(7),
16911700 (2005).
132 Clayton AL, Rose S, Barratt MJ, Mahadevan
LC. Phosphoacetylation of histone H3 on
c-fos- and c-jun-associated nucleosomes upon
gene activation. EMBOJ. 19(14), 37143726
(2000).
133 Cheung P, Tanner KG, Cheung WL, Sassone-
Corsi P, Denu JM, Allis CD. Synergistic
coupling of histone H3 phosphorylation and
acetylation in response to epidermal growth
factor stimulation. Mol. Cell 5(6), 905915
(2000).
134 Crosio C, Heitz E, Allis CD, Borrelli E,
Sassone-Corsi P. Chromatin remodeling and
neuronal response: multiple signaling
pathways induce specific histone H3
modifications and early gene expression in
hippocampal neurons. J.Cell Sci. 116(Pt 24),
49054914 (2003).
ro
135 Chandramohan Y, Droste SK, Arthur JS,
Reul JM. The forced swimming-induced
behavioural immobility response involves
histone H3 phospho-acetylation and c-Fos
induction in dentate gyrus granule neurons
rP
via activation of the N-methyl-d-aspartate/
extracellular signal-regulated kinase/mitogen-
and stress-activated kinase signalling pathway.
Eur. J.Neurosci. 27(10), 27012713 (2008).
136 Chandramohan Y, Droste SK, Reul JM.
Novelty stress induces phospho-acetylation of
histone H3 in rat dentate gyrus granule
neurons through coincident signalling via the
N-methyl-D-aspartate receptor and the
glucocorticoid receptor: relevance for c-fos
induction. J.Neurochem. 101(3), 815828
(2007).
137 Collins A, Hill LE, Chandramohan Y,
Whitcomb D, Droste SK, Reul JM. Exercise
improves cognitive responses to psychological
stress through enhancement of epigenetic
mechanisms and gene expression in the
dentate gyrus. PLoS ONE 4(1), e4330 (2009).
138 Papadopoulos A, Chandramohan Y, Collins
A, Droste SK, Nutt DJ, Reul JM. GABAergic
control of novelty stress-responsive epigenetic
and gene expression mechanisms in the rat
dentate gyrus. Eur. Neuropsychopharmacol.
21(4), 316324 (2011).
139 McEwen BS. Stress and hippocampal
plasticity. Annu. Rev. Neurosci. 22, 105122
(1999).
140 Reul JM, Hesketh SA, Collins A, Mecinas
MG. Epigenetic mechanisms in the dentate
gyrus act as a molecular switch in
hippocampus-associated memory formation.
Epigenetics 4(7), 434439 (2009).
141 Gutierrez-Mecinas M, Trollope AF, Collins A
etal. Long-lasting behavioral responses to
stress involve a direct interaction of
Epigenomics (2013) 5(2)
glucocorticoid receptors with ERK1/2-MSK1-
Elk-1 signaling. Proc. Natl Acad. Sci. USA
108(33), 1380613811 (2011).
142 Nestler EJ, Hyman SE. Animal models of
neuropsychiatric disorders. Nat. Neurosci.
13(10), 11611169 (2010).
143 Tsankova NM, Berton O, Renthal W,
KumarA, Neve RL, Nestler EJ. Sustained
hippocampal chromatin regulation in a
mouse model of depression and
antidepressant action. Nat. Neurosci. 9(4),
519525 (2006).
144 Tsankova NM, Kumar A, Nestler EJ. Histone
modifications at gene promoter regions in rat
hippocampus after acute and chronic
electroconvulsive seizures. J.Neurosci.
24(24), 56035610 (2004).
of
145 Renthal W, Maze I, Krishnan V etal.
Histone deacetylase 5 epigenetically controls
behavioral adaptations to chronic emotional
stimuli. Neuron 56(3), 517529 (2007).
146 Covington HE, 3rd, Maze I, Laplant QC
etal. Antidepressant actions of histone
deacetylase inhibitors. J.Neurosci. 29(37),
1145111460 (2009).
147 Laplant Q, Vialou V, Covington HE 3rd etal.
Dnmt3a regulates emotional behavior and
spine plasticity in the nucleus accumbens.
Nat. Neurosci. 13(9), 11371143 (2010).
148 Elliott E, Ezra-Nevo G, Regev L, Neufeld-
Cohen A, Chen A. Resilience to social stress
coincides with functional DNA methylation
of the Crf gene in adult mice. Nat. Neurosci.
13(11), 13511353 (2010).
149 Wilkinson MB, Xiao G, Kumar A etal.
Imipramine treatment and resiliency exhibit
similar chromatin regulation in the mouse
nucleus accumbens in depression models.
J.Neurosci. 29(24), 78207832 (2009).
150 Covington HE, 3rd, Maze I, Sun H etal. A
role for repressive histone methylation in
cocaine-induced vulnerability to stress.
Neuron 71(4), 656670 (2011).
151 Maze I, Covington HE 3rd, Dietz DM etal.
Essential role of the histone methyltransferase
G9a in cocaine-induced plasticity. Science
327(5962), 213216 (2010).
152 Hunter RG, Mccarthy KJ, Milne TA,
PfaffDW, McEwen BS. Regulation of
hippocampal H3 histone methylation by acute
and chronic stress. Proc. Natl Acad. Sci. USA
106(49), 2091220917 (2009).
153 Reed B, Fang N, Mayer-Blackwell B etal.
Chromatin alterations in response to forced
swimming underlie increased prodynorphin
transcription. Neuroscience 220, 109118
(2012).
154 Mcclintock B. The significance of responses of
the genome to challenge. Science 226(4676),
792801 (1984).
future science group
 Stress & anxiety across the lifespan: structural plasticity & epigenetic regulation
155 Hunter RG, Murakami G, Dewell S etal.
Acute stress and hippocampal histone H3
lysine 9 trimethylation, a retrotransposon
silencing response. Proc. Natl Acad. Sci. USA
109(43), 1765717662 (2012).
156 Rusiecki JA, Chen L, Srikantan V etal. DNA
methylation in repetitive elements and post-
traumatic stress disorder: a case-control study
of US military service members. Epigenomics
4(1), 2940 (2012).
157 Hedges DJ, Belancio VP. Restless genomes
humans as a model organism for
understanding host-retrotransposable element
dynamics. Adv. Genet. 73, 219262 (2011).
158 Uchida S, Nishida A, Hara K etal.
Characterization of the vulnerability to
repeated stress in Fischer 344 rats: possible
involvement of microRNA-mediated down-
regulation of the glucocorticoid receptor. Eur.
J.Neurosci. 27(9), 22502261 (2008).
159 Vreugdenhil E, Verissimo CS, Mariman R
etal. MicroRNA 18 and 124a down-regulate
the glucocorticoid receptor: implications for
glucocorticoid responsiveness in the brain.
Endocrinology 150(5), 22202228 (2009).
160 Meerson A, Cacheaux L, Goosens KA,
Sapolsky RM, Soreq H, Kaufer D. Changes
in brain MicroRNAs contribute to cholinergic
stress reactions. J.Mol. Neurosci. 40(12),
4755 (2010).
161 Haramati S, Navon I, Issler O etal.
MicroRNA as repressors of stress-induced
ho
anxiety: the case of amygdalar miR-34.
J.Neurosci. 31(40), 1419114203 (2011).
162 Rinaldi A, Vincenti S, De Vito F etal. Stress
induces region specific alterations in
microRNAs expression in mice. Behav. Brain
Res. 208(1), 265269 (2010).
ut
163 Babenko O, Golubov A, Ilnytskyy Y,
Kovalchuk I, Metz GA. Genomic and
Epigenomic responses to chronic stress
involve miRNA-mediated programming.
A
PLoS ONE 7(1), e29441 (2012).
164 Mongrain V, Hernandez SA, Pradervand S
etal. Separating the contribution of
glucocorticoids and wakefulness to the
molecular and electrophysiological correlates
of sleep homeostasis. Sleep 33(9), 11471157
(2010).
165 Rajasethupathy P, Antonov I, Sheridan R
etal. A role for neuronal piRNAs in the
epigenetic control of memory-related synaptic
plasticity. Cell 149(3), 693707 (2012).
166 Mccue AD, Nuthikattu S, Reeder SH, Slotkin
RK. Gene expression and stress response
mediated by the epigenetic regulation of a
transposable element small RNA. PLoS Genet.
8(2), e1002474 (2012).
167 Perdiguero E, Sousa-Victor P, Ballestar E,
Munoz-Canoves P. Epigenetic regulation of
myogenesis. Epigenetics 4(8), 541550 (2009).
future science group
168 Sanosaka T, Namihira M, Nakashima K.
Epigenetic mechanisms in sequential
differentiation of neural stem cells. Epigenetics
4(2), 8992 (2009).
169 Sapolsky RM, Krey LC, McEwen BS.
Corticosterone receptors decline in a site-
specific manner in the aged rat brain. Brain
Res. 289(12), 235240 (1983).
170 Sapolsky RM, Krey LC, McEwen BS. The
adrenocortical stress-response in the aged
male rat: impairment of recovery from stress.
Exp. Gerontol. 18(1), 5564 (1983).
171 Sapolsky RM, Krey LC, McEwen BS. The
neuroendocrinology of stress and aging: the
glucocorticoid cascade hypothesis. Endocr.
Rev. 7(3), 284301 (1986).
172 Garrido P. Aging and stress: past hypotheses,
of
present approaches and perspectives. Aging
Dis 2(1), 8099 (2012).
173 Lupien S, Lecours AR, Schwartz G etal.
Longitudinal study of basal cortisol levels in
ro
healthy elderly subjects: evidence for
subgroups. Neurobiol. Aging 17(1), 95105
(1996).
174 Foy MR, Baudry M, Foy JG, Thompson RF.
17beta-estradiol modifies stress-induced and
rP
age-related changes in hippocampal synaptic
plasticity. Behav. Neurosci. 122(2), 301309
(2008).
175 Lee SW, Clemenson GD, Gage FH. New
neurons in an aged brain. Behav. Brain Res.
227(2), 497507 (2012).
176 Burke SN, Barnes CA. Senescent synapses
and hippocampal circuit dynamics. Trends
Neurosci. 33(3), 153161 (2010).
177 Heyn H, Li N, Ferreira HJ etal. Distinct
DNA methylomes of newborns and
centenarians. Proc. Natl Acad. Sci. USA
109(26), 1052210527 (2012).
178 Dosunmu R, Alashwal H, Zawia NH.
Genome-wide expression and methylation
profiling in the aged rodent brain due to
early-life Pb exposure and its relevance to
aging. Mech. Ageing Dev. 133(6), 435443
(2012).
179 Thompson RF, Atzmon G, Gheorghe C etal.
Tissue-specific dysregulation of DNA
methylation in aging. Aging Cell 9(4),
506518 (2010).
180 Hernandez DG, Nalls MA, Gibbs JR etal.
Distinct DNA methylation changes highly
correlated with chronological age in the
human brain. Hum. Mol. Genet. 20(6),
11641172 (2011).
181 Numata S, Ye T, Hyde TM etal. DNA
methylation signatures in development and
aging of the human prefrontal cortex. Am.
J.Hum. Genet. 90(2), 260272 (2012).
182 Rao JS, Keleshian VL, Klein S, Rapoport SI.
Epigenetic modifications in frontal cortex
www.futuremedicine.com
Review
from Alzheimers disease and bipolar disorder
patients. Transl. Psychiatry 2, e132 (2012).
183 Anderson RM, Shanmuganayagam D,
Weindruch R. Caloric restriction and aging:
studies in mice and monkeys. Toxicol. Pathol.
37(1), 4751 (2009).
184 Chouliaras L, Van Den Hove DL, Kenis G
etal. Caloric restriction attenuates age-related
changes of DNA methyltransferase 3a in
mouse hippocampus. Brain Behav. Immun.
25(4), 616623 (2010).
185 Patel NV, Finch CE. The glucocorticoid
paradox of caloric restriction in slowing brain
aging. Neurobiol. Aging 23(5), 707717
(2002).
186 McEwen BS. Plasticity of the hippocampus:
adaptation to chronic stress and allostatic
load. Ann. NY Acad. Sci. 933, 265277
(2001).
187 Szulwach KE, Li X, Li Y etal. 5-hmC-
mediated epigenetic dynamics during
postnatal neurodevelopment and aging. Nat.
Neurosci. 14(12), 16071616 (2011).
188 Chen H, Dzitoyeva S, Manev H. Effect of
aging on 5-hydroxymethylcytosine in the
mouse hippocampus. Restor. Neurol. Neurosci.
30(3), 237245 (2012).
189 Graff J, Rei D, Guan JS etal. An epigenetic
blockade of cognitive functions in the
neurodegenerating brain. Nature 483(7388),
222226 (2012).
190 Zeng Y, Tan M, Kohyama J etal. Epigenetic
enhancement of BDNF signaling rescues
synaptic plasticity in aging. J.Neurosci.
31(49), 1780017810 (2011).
191 Peleg S, Sananbenesi F, Zovoilis A etal.
Altered histone acetylation is associated with
age-dependent memory impairment in mice.
Science 328(5979), 753756 (2010).
192 Walker MP, Laferla FM, Oddo SS, Brewer
GJ. Reversible epigenetic histone
modifications and Bdnf expression in neurons
with aging and from a mouse model of
Alzheimers disease. Age (Dordr.) doi:10.1007/
s11357-011-9375-5 (2012) (Epub ahead of
print).
193 Castellano JF, Fletcher BR, Kelley-Bell B,
Kim DH, Gallagher M, Rapp PR. Age-related
memory impairment is associated with
disrupted multivariate epigenetic
coordination in the hippocampus. PLoS ONE
7(3), e33249 (2012).
194 Doyle JP, Dougherty JD, Heiman M etal.
Application of a translational profiling
approach for the comparative analysis of CNS
cell types. Cell 135(4), 749762 (2008).
195 Heiman M, Schaefer A, Gong S etal. A
translational profiling approach for the
molecular characterization of CNS cell types.
Cell 135(4), 738748 (2008).
17
Review Hunter & McEwen
196 Veenema AH. Early life stress, the
development of aggression and
neuroendocrine and neurobiological
correlates: what can we learn from animal
models? Front. Neuroendocrinol. 30(4),
497518 (2009).
197 Kolber BJ, Wieczorek L, Muglia LJ.
Hypothalamic-pituitary-adrenal axis
dysregulation and behavioral analysis of
mouse mutants with altered glucocorticoid or
mineralocorticoid receptor function. Stress
11(5), 321338 (2008).
ho
ut
A
18
198 Zhang D, Yu ZY, Cruz P, Kong Q, Li S, Kone
BC. Epigenetics and the control of epithelial
sodium channel expression in collecting duct.
Kidney Int. 75(3), 260267 (2009).
199 ENCODE Project Consortium. The
ENCODE (ENCyclopedia Of DNA
Elements) Project. Science 306(5696),
636640 (2004).
200 Spannhoff A, Hauser AT, Heinke R, Sippl W,
Jung M. The emerging therapeutic potential
of histone methyltransferase and demethylase
inhibitors. ChemMedChem. 4(10), 15681582
(2009).
of
ro
rP
Epigenomics (2013) 5(2)
201 Kubicek S, OSullivan RJ, August EM etal.
Reversal of H3K9me2 by a small-molecule
inhibitor for the G9a histone
methyltransferase. Mol. Cell 25(3), 473481
(2007).
202 Hunter RG. Epigenetic effects of stress and
corticosteroids in the brain. Front. Cell.
Neurosci. 6, 18 (2012).
203 Magarinos AM, McEwen BS, Flugge G,
Fuchs E. Chronic psychosocial stress causes
apical dendritic atrophy of hippocampal CA3
pyramidal neurons in subordinate tree shrews.
J.Neurosci. 16(10), 35343540 (1996).
future science group